Is STAT5B p.Ala729Ser (c.2185G>T) pathogenic?

STAT5B p.Ala729Ser (c.2185G>T) is classified Likely benign in STAT5B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0904); Rare (popmax 0.18%, eas); Associated with growth hormone insensitivity with immune dysregulation 1, autosomal recessive.

What condition is associated with STAT5B p.Ala729Ser (c.2185G>T)?

STAT5B p.Ala729Ser (c.2185G>T) is associated with growth hormone insensitivity with immune dysregulation 1, autosomal recessive (ClinVar).

How common is STAT5B p.Ala729Ser (c.2185G>T) in the general population?

STAT5B p.Ala729Ser (c.2185G>T) is rare (popmax 0.18%, eas) (gnomAD).

How is Laron syndrome with immunodeficiency inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about STAT5B p.Ala729Ser (c.2185G>T)?

AlphaMissense predicts likely benign (score 0.0904) — an in-silico prediction, not a clinical call.

STAT5B p.Ala729Ser

c.2185G>T · rs200042237 · VCV466224

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0904 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.18%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

growth hormone insensitivity with immune dysregulation 1, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.0904	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -5.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 696 bp · p 0.0011 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.18% East Asian · 81/44,898 alleles

Filtering AF 0.149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.00948% 153/1,614,112 alleles · rare exomes 134/1,461,876 · genomes 19/152,236 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.18%	554
Finnishnot grpmax-eligible	0.0656%	1,525
European (non-Finnish)	0.00237%	42,144
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,092

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: STAT5B
Protein: p.Ala729Ser
Coding: c.2185G>T
MANE Select: NM_012448
dbSNP: rs200042237
Type: single nucleotide variant
Location: chr17:42202392 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.90 · 2 PDB

Full STAT5B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

growth hormone insensitivity with immune dysregulation 1, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Laron syndrome with immunodeficiency (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

STAT5B p.Ala729Thr Uncertain significance ★ ⚠ same residue
STAT5B p.Ala729Val Uncertain significance ★ ⚠ same residue
STAT5B c.1906+1G>A Likely pathogenic ★★ same condition
STAT5B p.Ala20Glu Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala20Val Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala213Gly Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala213Ser Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala723Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/stat5b-p-ala729ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown